Developmental variations in metabolic capacity of flavin-containing mono-oxygenase 3 in childhood

Authors


Professor J. Steven Leeder, Division of Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, MO 64108, USA. Tel.: + 1 816 234 3088 Fax: + 1 816 855 1958 E-mail: sleeder@cmh.edu

Professor Hiroshi Yamazaki, Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. Tel.: + 81 42 721 1406 Fax: + 81 42 721 1406 E-mail: hyamazak@ac.shoyaku.ac.jp

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The function of the human flavin-containing mono-oxygenase (FMO) has been shown to have large inter-individual variation related to trimethylaminuria.

WHAT THIS STUDY ADDS

• The study suggests that a developmental variation in functional metabolic capacity of FMO3 is occurring in childhood on the basis of in vivo phenotyping tests and in vitro liver microsomal determinations.

AIM The aim of this study was to investigate intra- and inter-individual variations of functional metabolic capacity of flavin-containing mono-oxygenase (FMO) during childhood using trimethylamine N-oxygenation as a probe reaction.

METHODS Trimethylamine N-oxygenation functional activity and presence of FMO1 (fetal form), FMO3 (adult form), and FMO5 (endogenous form) were immunochemically determined and compared in human liver microsomes obtained from children at various ages. As a control, the same parameters were studied with recombinant FMO1, FMO3 and FMO5 proteins as enzyme sources. Developmental variation in functional metabolic capacity of FMO was estimated by measuring urinary trimethylamine and its N-oxide in several individuals at different ages and in a group of 77 subjects in childhood.

RESULTS There was a significant correlation between trimethylamine N-oxygenation functional activity and FMO3 expression levels in human liver microsomes (r= 0.71, P < 0.05, n= 9). Trimethylamine N-oxygenation was catalyzed largely by FMO3 and not by FMO1 or FMO5. On the basis of analysis of intra-individual observations and collective urine samples under daily dietary conditions it was possible that neonates or infants harbouring at least one non-inactive-allele of the FMO3 gene could have developmental FMO3 metabolic capacity in childhood.

CONCLUSIONS Developmental variations in functional metabolic capacity of FMO3 in childhood were shown both on the basis of in vivo phenotyping tests and in in vitro liver microsomal determinations.

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